Is target sign (bull’s eye appearance) associated with adverse outcomes in COVID-19 patients? A case series and literature review

Background: In COVID-19 pneumonia, chest CT scan plays a crucial role in diagnosing and closely monitoring lung parenchyma. The main reportedly chest CT features of novel coronavirus pneumonia (NCP) have been fully discussed in the literature, but there is still a paucity of reports on uncommon CT manifestations. Case presentation: Herewith, we have reported ten rRT-PCR confirmed COVID-19 patients with CT target signs (bull’s eye appearance); additionally, we have reviewed previously reported cases. Reviewing the literature, we found eight COVID-19 patients with target sign in the literature. 18 patients were included with a median age of 43. 11 (61%) patients were males. In 87% of patients, the lesions developed within the second-week post symptom onset. These patients mostly experienced an extended hospital stay (median = 10 days), with 53.8% of cases being admitted in ICU. The in-hospital mortality rate was 23%. Conclusion: Our findings indicate that lesions with a bull’s eye appearance are not significantly associated with higher mortality in hospitalized COVID-19 patients.

I n mid-December 2019, novel coronavirus emerged in Wuhan, China, and then it quickly spread around China and throughout the world. Coronavirus disease 2019 (COVID-19) is a novel infectious disease that mainly causes inflammation in the respiratory system (1). Therefore, chest imaging is of diagnostic and monitoring value to detect and closely monitor lung parenchyma disease. The main reportedly chest CT features of novel coronavirus pneumonia (NCP) are multifocal, peripheral ground-glass opacity (GGO), consolidation, or a mixture of both with a basal dominancy, with or without less common findings such as the reverse halo sign (RHS) -a central area of GGO surrounded by a denser rim of consolidation-and crazy paving (2). Although typical clinical and para-clinical findings of NCP have been thoroughly investigated, there is still a paucity of reports on uncommon CT manifestations of NCP. Hereby, we present eight rRT-PCR confirmed COVID-19 patients with a target sign, a new unusual and yet specific tomographic sign in NCP; a literature review on formerly reported cases with this CT feature will be provided also.

Case presentation
This retrospective observational study was approved by the local Institutional Review Board. The informed consent requirement was waived by the ethics committee of our institute (IR.TUMS.VCR.REC.1399.144).
All on-admission chest CT scan of rRT-PCR confirmed COVID-19 infected patients, who were admitted to our tertiary referral hospital (with daily admission of about 15 COVID-19 patients) between February 2020 and February 2021 underwent review by an expert radiologist. Among them, all patients with opacities, suspicious for a target sign or bull's eye appearance were included.
Our systematic search was performed on relevant data through PubMed/MEDLINE and Google scholar. Articles published up to February 2021, using the search line of "target" or "target sign" or "bull's eye" plus "COVID-19" or "novel coronavirus pneumonia" or "SARS-CoV2" were extracted. We included all studies enrolling rRT-PCR confirmed COVID-19 cases with bull's eye appearance or target sign being reported on their chest CT scan. A total of four studies with eight relevant cases were found (table 1).

Discussion
Looking into the archived chest CT scan of large series of hospitalized COVID-19 patients, we encountered ten cases with target lesions. Although this finding has been recently noticed and discussed in the literature, interestingly, most of these images were taken from March to November 2020 that waives the possibility of new variants of SARS-CoV-2 to be the causative pathogen. Pooling results from our study and previously reported cases, it appears that male sex and lower calcium level might increase the likelihood of target sign development in chest CT. Although COVID-19 prevalence is gender-independent, more extensive pulmonary involvement and more critical disease has been observed in infected males based on previous studies (3). Lower calcium level has also been found to be associated with severe disease and poor clinical outcome, as calcium is believed to have a role in cytokine release regulation (4,5).
Target sign mostly appears in the second week of symptom onset while there is moderate-to-severe pulmonary involvement. Parenchymal band and vacuolar sign were the most common simultaneous additional findings in CT images, indicating the later phases of COVID-19. According to the literature, pulmonary involvement begins with GGOs in the first stage (0-4 days), and is followed by crazy paving and consolidation in the second (5-8 days) and third (9-13 days) stages, respectively. Reportedly, pulmonary involvement peaks in the second week of disease course (6).
Additionally, and of note, patients with this new tomographic sign stay in hospital for a longer period of time (median = 10 days) with a higher rate of ICU admission, aggressive treatment, and mechanical ventilation. The rate of ICU admission and in-hospital mortality in COVID-19 patients with target sign in chest CT were approximately 53.8% and 23%, respectively. On the other hand, the global statistics revealed that the rate of ICU admission and inhospital mortality in COVID-19 patients are about 32% and 30%, respectively (7)(8)(9). Accordingly, although rare, patients with target-like opacities should receive intensive care and aggressive treatments to minimize the adverse events. However, the in-hospital mortality rate was not significantly higher than that of COVID-19 infected patients without targetoid lesion(s) in chest CT.
Different COVID-19 radiologic manifestations in plain chest x-ray and CT scan have been fully discussed (10). According to the RSNA consensus, the most common typical CT manifestations of NCP are single/multiple peripheral bilateral patch (es) of GGO with or without consolidation, multifocal GGO of rounded morphology, crazy-paving, and RHS (2). Nevertheless, a growing number of case reports are offering atypical imaging features and specific signs in NCP. Some described radiology signs in COVID-19 pneumonia are white lung sign (diffuse opacities), halo sign (a nodule surrounded by GGO), RHS (rounded GGO surrounded by a ring of consolidation), bat wing sign (bilateral peripheral opacities), Rosa roxburghii sign (focal nodular GGO), and the gypsum sign (patchy bilateral consolidation with various density) (11). The target sign corresponds to a central rounded opacity surrounded by a polygonal ring-like opacity indicative of organizing pneumonia (12). So far, only eight cases of COVID-19 patients with target signs have been reported (11)(12)(13)(14) (table 1). Although the appearance is distinctive, RHS and target signs could be misinterpreted in daily practice. The opacity outline is rounded or oval shaped in RHS, but polygonal in the target sign. The polygonal outline represents perilobular pattern, and is suggestive of organizing pneumonia (15); while the central nodular opacity indicates perivascular inflammation. Denser central opacities might at least partly reflect the focal enlargement of the pulmonary artery (16).Although RHS and target sign are relatively similar imaging manifestations and both indicate organizing pneumonia, target sign is more specific for COVID-19 (17). Patients with target sign should be carefully evaluated for COVID-19 in a suggestive clinical setting, as it should raise a flag to radiologists. Nevertheless, conducting large-scale investigations evaluating the prevalence of target sign in pneumonias caused by various pathogens are recommended to validate the specificity of this newly introduced tomographic sign in diagnosing COVID-19 induced pneumonia. Definitely drawing a conclusion from a limited population is subject to uncertainty and further studies using meta-analysis are warranted to confirm our findings.
In conclusion, in COVID-19 patients target opacities more likely develop in males and during second week after symptom onset. Patients with this specific chest CT feature experience an extended hospital stay and frequently require intensive care, but this sign is probably not associated with increased mortality rate.